The Role of Hypoxia-Regulated MicroRNAs (Hypoxamirs) in Tumor-Associated Macrophage Polarization: A Systematic Review

Hypoxia within the tumor microenvironment (TME) triggers the exosomal transfer of microRNAs (hypoxamirs) that reprogram tumor-associated macrophages (TAMs) toward a pro-tumorigenic M2 phenotype. This systematic review defines the molecular pathways and clinical consequences of the hypoxamir-TAM axis across solid malignancies to guide therapeutic translation. A systematic search of PubMed, Embase, and Cochrane library was conducted through February 1, 2026. Following PRISMA 2020 guidelines, 17 studies were included for analysis. Methodological quality was evaluated using the standard Office of Health Assessment and Translation (OHAT) tool. Analysis identified two primary regulatory tracks: a signaling axis mediated by targets such as PTEN, IRF1, and PHLPP2, and a metabolic axis driven by miR-210, let-7a, and miR-30c targeting the iron-sulfur cluster assembly protein (ISCU). These coordinated pathways drive an "angiogenic switch," facilitate "metabolic migration," and induce significant resistance to chemotherapies, including gemcitabine and temozolomide. Fourteen studies achieved a high-confidence Tier 1 OHAT rating. The hypoxamir-TAM axis is a fundamental driver of immune evasion and therapeutic failure. Targeting this dual-axis framework offers a viable strategy for restoring anti-tumor immunity, while circulating hypoxamirs represent high-value liquid biopsy biomarkers for real-time TME monitoring.